We made notable progress in finding the genetic causes of adolescent-onset idiopathic generalized epilepsy (IGE). During the last grant period, we: 1) Found 5 IGE-linked loci on chrs. 5p, 5q, 6, 8, & 18. 2) Identified the chr. 18 gene as malic enzyme 2 (ME2), conferring susceptibility to several forms of IGE. 3) Identified case- control sequence differences in intron 1 of ME2. 4) Showed that inhibiting ME2 in brain increases neuroexcitability. 5) Identified the HLA-linked JME chr. 6 locus (EJM1) as the BRD2 gene. 6) Found maternal inheritance of EJM1 in linkage data and population data. 7) Showed BRD2 contains unusual intronic sequences with GC-rich regions seen in other imprinted genes. 8) Development of a BRD2 knockout mouse. 9) Showed BRD2 is highly expressed in brain during development using in-situ hybridization. 10) Found a childhood absence-specific association on chr. 5p in both case-control and family based data. We will exploit these findings to accomplish the following new aims: 1) Categorize SNPs in intron 1 of ME2 to identify susceptbility genotypes; 2) Analyze mRNA processing in ME2 to test the intron 1finding. 3) Study the enzymatic activity of ME2 derived from IGE patients and compare to activity from control subjects. 3) Test for ME2 expression variants in brain. 4) Test for interaction between the identified genes using SNP and haplotype data. 5) Identify genes on chromosomes 5 and 8. 6) Test if identified genes are IGE susceptibility loci in non-European ethnic groups by looking for association in African-American and Central/South American-origin IGE patients. 7) Determine whether ME2 increases susceptibility to other forms of idiopathic epilepsy (e.g. Rolandic, childhood absence, etc.). The identification of two, and soon a third (the 5p gene), IGE susceptibility genes suggests that we can, in the next grant period, come closer than ever before to understanding some causes of IGE. The ME2 locus findings especially may suggest new directions for epilepsy drug development.